According to a patient survey carried out by the Ministry of Health, Labour and Welfare of Japan in 2002, the total number of Japanese diabetes patients is 2.28 million. According to a diabetes fact-finding survey carried out in the same year, the combined total of “people strongly suspected of having diabetes” and “people for whom the possibility of diabetes cannot be denied” has increased to 16.20 million, meaning that diabetes is a problem.
Japanese people have a genetic factor for a weak insulin secretory capacity, and thus the Japanese domestic market is centered on insulin hyposecretion. However, due to the trend toward a more Western diet, recent years have seen a gradual increase in the number of patents with insulin resistance. Therefore, there is a need for drugs which can be expected to be effective against both insulin hyposecretion and insulin resistance.
Glucokinase (GK), which catalyzes the phosphorylation of glucose, functions as a glucose sensor in the body, and increases the secretion of insulin and the utilization of glucose in the liver during periods of high glucose levels. Diabetic patients are unable to normally maintain glucose homeostatis in their bodies. Thus, by activating GK, insulin secretion in the pancreas, which is glucose concentration dependent, is promoted. This has a dual action of increasing the utilization of glucose in the liver and suppressing the release of glucose. As a result, blood glucose decreases (Non-Patent Documents 1 to 3). Therefore, it is desirable to provide a GK activator which exhibits an effect as a diabetes drug on both insulin hyposecretion (pancreatic effect) and insulin resistance (hepatic effect).
Examples of known GK activators include various amide compounds (Patent Documents 11 to 19) such as arylcycloalkylpropionamides (Patent Document 1), 2,3-disubstituted transolefinic N-heteroaromatic ring—or ureidopropionic amides (Patent Document 2), alkynylphenyl heteroaromatic amides (Patent Document 3), hydantoins (Patent Document 4), substituted phenylacetamides (Patent Document 5), para-alkyl, allyl, cycloheteroalkyl or heteroaryl (carbonyl or sulfonyl) amine substituted phenylamides (Patent Document 6), alpha-acyl and alpha-heteroatom substituted benzene acetamides (Patent Document 7), tetrazolylphenylacetamides (Patent Document 8), fused heteroaromatic compound (Patent Document 9), and phenylacetamides having a cycloalkane with a single carbon atom substituted or heterocyclic ring (Patent Document 10). However, there has been no disclosure of GK activators in which two fluorine atoms are substituted on different carbon atoms of a cyclopentyl group.
[Patent Document 1] WO2000/058293 Pamphlet
[Patent Document 2] WO2001/044216 Pamphlet
[Patent Document 3] WO2001/083465 Pamphlet
[Patent Document 4] WO2001/083478 Pamphlet
[Patent Document 5] WO2001/085706 Pamphlet
[Patent Document 6] WO2001/085707 Pamphlet
[Patent Document 7] WO2002/008209 Pamphlet
[Patent Document 8] WO2002/014312 Pamphlet
[Patent Document 9] WO2002/046173 Pamphlet
[Patent Document 10] WO2003/095438 Pamphlet
[Patent Document 11] WO2004/052869 Pamphlet
[Patent Document 12] WO2004/072031 Pamphlet
[Patent Document 13] WO2004/072066 Pamphlet
[Patent Document 14] WO2005/103021 Pamphlet
[Patent Document 15] WO2006/016174 Pamphlet
[Patent Document 16] WO2006/016178 Pamphlet
[Patent Document 17] WO2006/016194 Pamphlet
[Patent Document 18] WO2006/059163 Pamphlet
[Patent Document 19] U.S. Pat. No. 6,911,545
[Non-Patent Document 1] Diabetes 45, 223-241 (1996)
[Non-Patent Document 2] Diabetes 41, 792-806 (1992)
[Non-Patent Document 3] FASEB J. 10, 1213-1218 (1996)